The goal of this project is to create noninvasive methodology to image the connectional neuroanatomy of the human brain using diffusion MRI. Two recent developments make this possible. First, we have shown in macaque that every region of the cerebral cortex reliably gives rise to a predictable number of fiber tracts connecting it with unique sets of neuronal subpopulations distributed within cortical and subcortical regions. Second, we have shown, also in macaque, that novel forms of high angular resolution diffusion spectrum MRI (DSI) have the unique capacity to define connectional neuroanatomy non-invasively. The goal of the present project is to define, for the first time, the connectional neuroanatomy of the monkey brain non-invasively, and to build a bridge from the macaque brain to the human brain in order to accomplish a previously impossible goal - the determination of connectional neuroanatomy in the human brain. To achieve this goal, three steps are necessary. First, we will validate diffusion MRI in macaque by comparison to the gold standard of isotope tract tracer injections, the tracer injections and MRI to be performed in the same animals. The technical parameters that optimally and most accurately replicate the findings of the tract tracer studies will be determined, and potential sources of MRI error quantified and minimized. Second, post-mortem human brains will be imaged to achieve the highest possible resolution of these human brains, with the aim of replicating the mandatory principles of organization of the white matter pathways identified as defining the connections of the monkey brain. Next, the brains of living human subjects will be imaged, to attempt to replicate the findings in the post- mortem specimens, in order to establish the limitations of the methodology in vivo. To convey this technology into the broader imaging arena, we will investigate the hypothesis that structural and functional connectivity are correlated by comparing the results with those of resting state connectivity in the living human brain. PUBLIC HEALTH RELEVANCE: The goal of this study is to develop and validate scientific methods for the study of the wiring and connections of the human brain. We will first use MRI and conventional tract tracing techniques in the monkey brain to optimize our MRI methods, and we will then study brains of people who are deceased, and also the brains of healthy human volunteers, to identify how these neural circuits are organized in the human. These studies have potential to provide new and valuable information about the human nervous system. This information is essential for understanding normal development; developmental disorders such as autism; neurological illnesses such as Alzheimer disease, multiple sclerosis, and traumatic brain injury; and psychiatric diseases such as schizophrenia.